In late years, the number of diabetic patients has been increasing due to westernization of dietary habits, chronic lack of exercise and so on. Decrease in insulin secretion and insulin sensitivity is observed in diabetic patients, which is caused by chronic hyperglycosemia, further causes elevation of blood sugar level and leads to aggravation of symptoms. Biguanide drugs, sulfonylurea drugs, glycosidase inhibitors, insulin sensitizers, etc., have been used as therapeutic drugs for diabetes. However, side effects such as lactic acidosis as for biguanide drugs, hypoglycemia as for sulfonylurea drugs, diarrhea as for glycosidase inhibitors have been reported, and now development of therapeutic drugs for diabetes according to new action mechanism different from these drugs is eagerly demanded.
It has been reported that Phloridzin, which is a naturally-occurring glucose derivative, inhibits sodium dependent glucose cotransporter 2 (SGLT2) occurring in S1 site of the renal proximal tubule, and thereby inhibits reabsorption of excessive glucose in the kidney, promotes glucose excretion, and exhibits hypoglycemic action (refer to Non-Patent Document 1). Thereafter, up to the present, studies on the therapeutic drugs for diabetes based on SGLT2 inhibition has been extensively performed.
For example, compounds usable as inhibitors of SGLT2 are reported in JP 2000-080041 A (Patent Document 1), WO01/068,660 (Patent Document 2), WO04/007,517 (Patent Document 3), etc. However, Phloridzin and the compounds described in the above-mentioned patent applications are considered to be problematic in that when they are orally administered, they are readily hydrolyzed by glycosidase and the like present in the small intestine and the pharmacological effect thereof immediately disappears. In addition, as for Phloridzin, there has been reported that phloretin, which is the aglycone moiety thereof, strongly inhibits a sugar transporter of the facilitated diffusion type and causes bad influences such that the glucose concentration in brain decreases when phloretin is administered to a rat vein (for example, refer to Non-Patent Document 2).
Therefore, attempts to convert the compounds to prodrugs have been made for the purpose of preventing such decomposition and improving absorption efficiency. However, although it is desirable that the administered prodrugs are suitably metabolized and changed into an active compound in or in the vicinity of the target organ, there are so various metabolic enzymes in the living body and there are so many differences among individuals that stable action cannot be exhibited in many cases. Attempts to convert the glycoside bond of the compound to a carbon-carbon bond have been also made (refer to Patent Documents 4 to 21), but further improvement is demanded in the characteristics as pharmaceutical agents including activity and metabolic stability.
[Patent Document 1]                JP 2000-080041 A        
[Patent Document 2]                International Publication WO01/068660        
[Patent Document 3]                International Publication WO04/007517        
[Patent Document 4]                US Patent Application Pub. No. 2001/041,674        
[Patent Document 5]                US Patent Application Pub. No. 2002/137,903        
[Patent Document 6]                International Publication WO01/027,128        
[Patent Document 7]                International Publication WO02/083066        
[Patent Document 8]                International Publication WO04/013118        
[Patent Document 9]                International Publication WO03/099836        
[Patent Document 10]                International Publication WO04/080990        
[Patent Document 11]                US Patent Application Pub. No. 2005/209,166        
[Patent Document 12]                International Publication WO05/085237        
[Patent Document 13]                International Publication WO05/085265        
[Patent Document 14]                International Publication WO05/012318        
[Patent Document 15]                International Publication WO05/012326        
[Patent Document 16]                US Patent Application Pub. No. 2006/063,722        
[Patent Document 17]                US Patent Application Pub. No. 2006/035,841        
[Patent Document 18]                US Patent Application Pub. No. 2006/074,031        
[Patent Document 19]                International Publication WO06/002,912        
[Patent Document 20]                International Publication WO06/008038        
[Patent Document 21]                International Publication WO06/010557        
[Non-Patent Document 1]                J. Clin. Invest., Vol. 93, page 397, 1994        
[Non-Patent Document 2]                Stroke, Vol. 14, page 388, 1983        